Cancer Prog Diagn, 2020 Volume 4(1): 87-91

Research Article

Cancer Prognostics and Diagnostics

Small Cell Carcinoma of Gall Bladder: A Rare Case and Review.Lava Krishna Kannappa1*, Sufian Khalid1, Noor Ul Ain Abid1, Monisha Chakravorty1, Risa Mosby1, Musthaq Shah1, Adegoke Oyegade1, Muhammad Ilyas Khan1, Dimitrios Papachristos1, Tawfiq Omar1, Chitakattil Oommen1, Danaradja Arumugam1

1 Department of General Surgery, Rotherham Hospital, United Kingdom.

Case Summary:64 year old, Asian female presented in emergency general surgery

department with one day history of right upper quadrant pain, prior to this admission, she was diagnosed of gallstones by ultrasound and was admitted with acute cholecystitis. She was due for laparoscopic cholecystectomy during her previous admission, but operation was postponed because of failed intubation. Her past medical history included Hypertension, Type 2 Diabetes Mellitus, Gastro-Oesophageal reflux disease, Hypertension, dyslipidaemia, Chronic Obstructed pulmonary disease, Gastritis, She was investigated for Anaemia by Esophagogastroduodenoscopy (OGD) and colonoscopy and a benign polyp was snared. OGD Showed gastritis and biopsy was positive for helicobacter pylori and was treated with triple therapy. The medications included anti hypertensives, Proton pump inhibitors and oral hypoglycaemic tablets. Clinical examination was tenderness in right upper quadrant and Murphy’s sign negative. Computer Tomography (CT) scan of the abdomen revealed a mass & the Patient was referred to MDT( Multi-disciplinary meeting) for further management Unfortunately, While on chemotherapy, She passed away in June 2019.The blood results are as shown in the table 1. We present you a extremely rare case of small cell cancer of the gall bladder and present a brief review.

Radiology Investigations: Ultrasound Abdomen: Ultrasound report suggested abnormal Gallbladder with several calculi and irregular echogenic material. There was no biliary duct dilatation. The liver appeared overall with fatty infiltration. There were several reactive enlarged paraaortic lymph nodes. Pancreas visualization was difficult because of lymph nodes, pancreatic pathology was not excluded. Urgent CT (Computer Tomography) imaging of abdomen and pelvis and staging CT chest was suggested keeping in mind of Malignancy.

CT abdomen/pelvis showed large 9.5cm soft tissue mass centered around the gall bladder with apparent involvement of the second part of the duodenum and pancreatic head. Multiple pathological upper

*Corresponding author: Lava Krishna Kannappa, Department of General Surgery, Rotherham Hospital, United Kingdom, Tel: +44 1709 820000; Fax: +44 1709 820000; E-mail: lavakrishna@yahoo.com

Received: January 13, 2020; Accepted: January 21, 2020; Published: January 24, 2020.

Copyright: © 2020 Lava Krishna Kannappa, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

abdominal lymph nodes. However, the CT chest was normal.

MRI (Magnetic resonance imaging) of liver with Gadolinium showed a bulky mass centered around the gall bladder with soft tissue infiltration into pancreatic head and second part of duodenum with possible focal involvement of the hepatic flexure. Later on, CT liver showed progression with CBD with portal vein compression.

The patient went on to have a gall bladder biopsy which revealed a diagnosis of small cell carcinoma of gall bladder. The CT and the histological findings with the images are as shown below for the case. Figure 1,2.

Histology Pictures:Figure 3-9.

Discussion: Gall bladder (GB) cancer is rare type of cancer with incidence of

around 220,000 new cases reported in the world in 2018. GB cancer is 17th and 18th most common cancer in men and women with high incidences predominantly in American–Indian, Chilean–Mapuche populations, as well as in the North of India [1,2]. The highest incidence

Hb 9.3 Eosinophils 0.2 ALT 60

WCC 6.20 Basophils 0.0 AST 150

Platelets 317 Glucose 5.7 GGT 517

RBC 0.28 Sodium 131 ALP 517

Haematocrit 85.0 Potassium 4.0 Total protein 65

MCV 28.4 Creatinine 90 Albumin 34

MCHC 334 eGFR 55 Globulin 31

RDW 14.6 Urea 5.6

Neutrophils 4.1 Urate 226

Monophils 0.4 Total Bilirubin 26

Table 1: Blood results on admission.

Figure 1: T2 contrast enhanced fat suppressed axial sequence demonstrating the gallbladder mass (*). Small arrows: gallbladder wall. S: Gall stones.

Citation: Lava Krishna Kannappa, Sufian Khalid, Noor Ul Ain Abid, Monisha Chakravorty, Risa Mosby, et al. (2020) Small Cell Carcinoma of Gall Bladder: A Rare Case and Review. Cancer Prog Diagn 4:119.

Cancer Prog Diagn, 2020 Volume 4(1): 88-91

in Europe was reported in Slovakia, Slovenia and Hungary. It was also noted to be having high incidence among American Indians and Alaskan natives compared to other ethnicities in USA [3]. GB cancer prevalence is about three times higher among women than men in all populations [4]. The GB cancer incidence rates among women worldwide were reported highest in Delhi (21.5/100,000), South

Karachi, Pakistan (13.8/100,000) and Quito, Equador (12.9/100,000) [2]. As per the College of American pathologist protocol (CAP)

Figure 2: Axial contrast enhanced CT demonstrating the extent of the gallbladder mass extending beyond the liver hilum (*). Small arrows demonstrate the gallbladder wall. Calcified stones are seen, but these are better depicted on the MRI sequence.

Figure 3: AE1/3 immunoslide showing tumour cells with strong uniform positive stainin

Figure 4: CD56 immunoslide showing tumour cells show characteristic strong positive uniform staining for the neuroendocrine marker CD56.

Figure 5, 6 & 7: Haematoxylin and eosin (H & E) slides at various magnifications of 4x, 10x and 40x. The core biopsy of gallbladder shows diffuse infiltration by sheets of small cell carcinoma cells with hyperchromatic nuclei, scanty cytoplasm, crushing artefact and frequent mitotic figures.

Figure 8: Synaptophysin immunoslide showing tumour cells show characteristic strong positive uniform staining for the neuroendocrine marker Synaptophysin.

Figure 9: TTF1 (Thyroid transcription factor-1) immunoslide showing tumour cells show negative staining for the lung tumour marker TTF1, thus confirming that the small cell carcinoma is not of lung origin.

Citation: Lava Krishna Kannappa, Sufian Khalid, Noor Ul Ain Abid, Monisha Chakravorty, Risa Mosby, et al. (2020) Small Cell Carcinoma of Gall Bladder: A Rare Case and Review. Cancer Prog Diagn 4:119.

Cancer Prog Diagn, 2020 Volume 4(1): 89-91

published in June 2017 describes the: histological grading into the following stages (Table 2)

Adenocarcinomas constitute the commonest and about 85% of all gall bladder cancers [1] and 15% constitute the rest of the histological types. Small cell Gallbladder cancer constitutes about 0.5% of the cancers [5]. Small cell GB cancer was first described by Albores-Saavedra et al in 1981 [6]. Small cell carcinomas also called oat cell carcinomas due to the cancer cells having a distinctive oat like shape. CAP guidelines for GB cancer in 2004 classified small cell cancer of GB as a separate entity, but this has changed in the subsequent guidelines issued by CAP, which classifies small and large cell GB cancer as of neuroendocrine Carcinoma(NEC) [7]. We discuss about the molecular pathogenesis of the Gall bladder cancer as shown below.

Molecular Pathogenesis of Gall Bladder Cancer: GBC develops due to series of step wise cascade of molecular

events in the cell leading to invasive Cancer. Roa et al (2006) study mentioned about the epithelial lesions leading to gall bladder cancer evolved from two distinct evolutionary models namely dysplasia and adenomas. The most important pathway being the Dysplasia model leading to carcinoma in situ (CIS) finally turning into invasive cancer with over 80% of GBC areas present adjacent to CIS and epithelial dysplasia. The adenomatous pathway having adenomatous remnants in the neighbouring mucosa to early carcinomas were noted in less than 3% of the cases.

The study also concluded that dysplasia-carcinoma pathway is the most plausible carcinogenic pathway for gall bladder cancer and would require a period of 10 years [8].

Wistuba et al (2004) mentioned about two pathways for development of GBC. The most common pathway prevalent in most part of the world seems to be cholelithiasis leading to chronic inflammation of gall bladder eventually leading to cancer. The proposed answers for gall stones leading to cancer has been proposed to be due to mechanical irritation to the mucosal surface of gall bladder and gall stones affect function by creating stasis due to delayed or incomplete emptying leading to inflammation and cancer. This pathway involved early onset of TP53 mutations and rare KRAS mutation and observed in studies done in Chile [9].

The second pathway more common in japan and china has been proposed due to anomalous pancreatobiliary duct junction (APBCJ) and has been associated in 17% of GBC in japan. In APBCJ ,the pancreatic and common bile duct join together before the duodenal wall leading to loss of control of sphincter of Oddi. This causes regurgitation of pancreatic juice into the gall bladder leading to stasis and irritation of gall bladder and finally causing premalignant

changes in the gallbladder epithelium leading to cancer [10]. This pathway involves early onset of KRAS mutations and late onset of TP53 mutations [11]. Figure 10.

Wistuba et al (2004) after microdissection of paraffin embedded tissues and applying molecular techniques proposed the multistage steps in the pathogenesis of GBC. The study mentioned about three stages in the multistep process. The first step involved include TP53 mutations, COX2 overexpression, mitochondrial DNA mutations and abnormal hypermethylation of promoters of various tumour-suppressor genes (TSGs).The second stage involved allelic loss at several chromosomal sites (in particular on the p arms of chromosomes 3 and 8). Late changes at the carcinoma in situ stage include inactivation of the fragile histidine triad (FHIT) and CDKN2A tumour-suppressor genes and losses at additional chromosomal regions, particularly on the q arms of chromosomes 9, 18 and 22.The last stage, tumour-specific changes occur, which are detected only in invasive tumours and include KRAS mutations. The three stage process is shown in the figure 11 below.

Risk factors for gall bladder cancer have been associated in various studies .The risk factors are as in the table 3 below:

Neuroendocrine tumours (NET) are a diverse group of cancers arising from neuroendocrine cells in the body and behave disparately in terms of their origin, clinical progression, treatment and their outcome [25]. The main primary sites are the gastrointestinal tract (62-67%) and the lung (22-27%) [26]. Primary NEC of the gall bladder is rare with 66% of the patients at diagnosis presenting with metastasis [27]. The term neuroendocrine carcinoma (NEC) differs from neuroendocrine tumour with respect to its poor differentiation and high tumour grade. Gallbladder NETs can be classified into four broad histological categories based on tumour differentiation and grade: (1) well-differentiated NETs (typical carcinoid), (2) well-differentiated neuroendocrine carcinoma (atypical or malignant

Adenocarcinoma Biliary typeAdenocarcinoma intestinal typeAdenocarcinoma gastric foveolar typeMucinous AdenocarcinomaClear cell AdenocarcinomaSignet ring cell carcinomaSquamous cell carcinomaAdenosquamous carcinomaUndifferentiated carcinomaNeuroendocrine carcinomaSmall cell Neuroendocrine carcinoma*Large cell Neuroendocrine carcinoma*Mixed Adenoneuroendocrine carcinoma*Intraductal Papillary neoplasm with an associated invasive componentMucinous Cystic neoplasm with an associated invasive component

Table 2: Histological Grading of Gall Bladder Cancer.

Subgroup * Figure 10: Two pathways for pathogenesis of GBC. (Adapted from Wistuba and gazdar).

Citation: Lava Krishna Kannappa, Sufian Khalid, Noor Ul Ain Abid, Monisha Chakravorty, Risa Mosby, et al. (2020) Small Cell Carcinoma of Gall Bladder: A Rare Case and Review. Cancer Prog Diagn 4:119.

Cancer Prog Diagn, 2020 Volume 4(1): 90-91

carcinoid), (3) poorly differentiated neuroendocrine carcinoma (high-grade carcinoma—small-cell/large-cell types), and (4) mixed exocrine-endocrine carcinomas [28]. Histologically, SCC is found on 0.5% of the cases of GB cancer with cells predominantly single and dispersed with scant to absent cytoplasm. Nucleus showed moderate anisonucleosis, salt and pepper chromatin, nuclear molding, necrosis, mitoses, and absence of nucleoli Smudge cells. When there were combination of adenocarcinoma and neuroendocrine elements, they were classified as Mixed Adenoneuroendocrine carcinoma [29].

Eltawil et al (2010) accessed the Surveillance, Epidemiology, and End Results (SEER) Program registry (1973 to 2005) and reported 278 cases of GB-NETs of the total 35,618 total NET’s found in the body. They also proposed NET in the gallbladder arise from either a multipotent stem cell or neuroendocrine cells in intestinal or gastric metaplasia of the gallbladder epithelium secondary to cholelithiasis/chronic inflammation. The NET of GB rarely exhibit carcinoid syndrome (1%) with a median survival was only 9.8 months among 278 cases of GB-NET and a 5 year survival for SCC at 0% [30].

Albores-Saavedra et al (2009) analysed the SEER program registry and evaluated the prevalence of Primary neuroendocrine tumours, which involve the gallbladder and extra hepatic biliary ducts (EHBDs) and found about 54 cases of SCCs in the GB. The study also evaluated the prevalence of female/male ratios for SCC in the GB and EHBD were 2.2 and 1.1, respectively, Mean age of presentation for SCC in GB is 68.4 years and a 10-year survival for SCC at 0% in the GB and

Figure 11: Multistage pathogenesis of Gallbladder Carcinoma associated with gallstones and inflammation. Adapted from Wistuba and gazdar [12].

Tamarkar et al. [13] Current smoker, Early Menarche (13 years), Parity > 3, Mustard oil, gall stone disease & illiteracy.

Jain et al. [14]

Fried foods, tobacco use, exposure to wood and coal dust, long interval between the meals, family history of gallstone disease, joint family, residence in Gangetic belt & Female sex.

Andia et al. [15]

Lithogenic genes, Chronic Salmonella typhi carriers, Occupation (oil, paper, chemical, shoe, textile, cellulose acetate fiber manufacturing industries & Miners exposed to Radom) & Obesity.

Mishra et al., Hassan et al. [16,17] Helicobacter pylori

Larsson et al., Tan et al. [18,19] Obesity and Female sexGu et al. [20] Type 2 diabetesShrikhande et al., Deihl et al. [21,22]

Stone size (>3 cm), increasing size, volume and weight, and number of the stones.

Berk et al. Porcelain gall bladder (Chronic inflammation leading to calcium deposition).

Nomura et al. [23] Anomalous Pancreatico- biliary junction pancreatic and biliary ducts join outside the duodenal wall

Pandey et al. [24] Apolipoprotein B (APOB Gene)

Table 3: Risk factors for GBC from various studies.

EHBD [31].

Carrera et al (2015) analysed the Case reports with SCC gallbladder between 1983 and 2014 of about 72 patients (49-Female, 23-Male). Of the 72 cases, About 52(72%) of the patients had Metastatic disease at diagnosis and 20 patients (19 clinical cases and 1 autopsy case) (38%) with local disease. Nineteen patients had diagnosis at autopsy. Presenting symptoms were common in both local and the metastasis group and were associated with abdominal pain, nausea, vomiting, jaundice, pruritus, and weight loss. The overall median survival was 13 months for both local and metastasis group. Eighteen patients underwent surgical resection with adjuvant treatment with chemotherapy (10) and chemo-radiotherapy (4) and radiation alone (1) with no overall benefit from adjuvant therapy. On the other hand, patients in the metastatic group who received chemotherapy had statistically improved median overall survival compared to patients who had no chemotherapy (13 versus 4 months). Carrera et al accept significant limitations in interpreting the results taking into consideration of the rarity of the disease [32].

Adachi et al (2016) review of 104 patients (82 –Pure small cell cancer, 22-Combined SCC) reported average age of diagnosis at 64 years with Male-to-female ratio of 1:1.9. Patients typically present with recurrent Right upper quadrant pain and less frequently as abdominal mass, Weight loss and ascites with a mean survival of 8 months [33]. The diagnosis of SCC GB with certainty is not possible, despite the imaging modalities of CT, Ultrasound, MRI and Positron emission tomography CT (PET-CT) available. Histopathological examination with immunohistochemical staining makes it a standard required to make a definitive diagnosis of SCC of GB [28]. Histopathologically, the tumour stain positive for Synaptophysin in 75 % of neuroendocrine carcinomas followed by chromogranin. If the SCC is functionally active or secretory neuroendocrine carcinoma in <1 percentage of cases, Urine 5-hydroxyindoleacetic acid (5-HIAA) and nuclear imaging studies (Octreotide scintigraphy or MIBG) may be useful to diagnose and respond to therapy [28].

The treatment of choice remains surgery for local disease from cholecystectomy alone to regional lymph node clearances and hepatic lobectomy with adjuvant chemotherapy giving a slight advantage. The disease most often found at stage 4 in about 67 % of the cases reduces the therapeutic interventions a limited option. In patients with metastatic disease, the mainstay therapy for intervention is chemotherapy with first choices of agents being cisplatin, etoposide, and 5-fluorouracil [33]. Other chemotherapy drugs like Topotecan, Irinotecan, Taxanes and Gemcitabine used with variable success rate [28]. Radiotherapy to bone and cord compression due to metastasis is well documented for its benefit is worth considering. Radiofrequency ablation, Transarterial chemoembolization and Transarterial radio ablation could also be considered in metastasis to liver for palliation [28]. There is dearth of large studies regarding the presentation, Treatment and outcome with respect to SCC of gallbladder due to its rarity and its atypical mode of presentation. Level one evidence like RCT’s would not be possible due difficulty in diagnosis. Few systematic reviews based on the case reports available in the literature with cases of small numbers sheds some light about the nature of the disease but with questionable accuracy. The limited knowledge available in the literature makes it very difficult to formulate a protocol in terms of arriving at consensus regarding the clinical management of SCC in GB. The need for large institutional studies is the need of the hour preferably in Asia and South America, which has the largest prevalence of the disease, is worth mentioning.

Conclusion:SCC of the gall bladder is a rare form of NEC, Which is high

grade, poorly differentiated with high metastasis at the diagnosis. Due to its rarity and the present lack of an accurate diagnosis other than

Citation: Lava Krishna Kannappa, Sufian Khalid, Noor Ul Ain Abid, Monisha Chakravorty, Risa Mosby, et al. (2020) Small Cell Carcinoma of Gall Bladder: A Rare Case and Review. Cancer Prog Diagn 4:119.

Cancer Prog Diagn, 2020 Volume 4(1): 91-91

biopsy or at the time of surgery, .There is little hope to diagnosing it early with radiological modalities due to its nonspecific nature of presentation. The advent of molecular medicine and the biomarkers should pave way of finding out the tumor early and in understanding of the biogenesis of the disease and its progression.

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